title: Copy number variation and selection during reprogramming to pluripotency.
abstract: The mechanisms underlying the low efficiency of reprogramming somatic cells into induced pluripotent stem (iPS) cells are poorly understood. There is a clear need to study whether the reprogramming process itself compromises genomic integrity and, through this, the efficiency of iPS cell establishment. Using a high-resolution single nucleotide polymorphism array, we compared copy number variations (CNVs) of different passages of human iPS cells with their fibroblast cell origins and with human embryonic stem (ES) cells. Here we show that significantly more CNVs are present in early-passage human iPS cells than intermediate passage human iPS cells, fibroblasts or human ES cells. Most CNVs are formed de novo and generate genetic mosaicism in early-passage human iPS cells. Most of these novel CNVs rendered the affected cells at a selective disadvantage. Remarkably, expansion of human iPS cells in culture selects rapidly against mutated cells, driving the lines towards a genetic state resembling human ES cells.
authors.affiliation: Samuel Lunenfeld Research Institute, Toronto, Ontario M5T 3H7, Canada.
authors.forename: Samer M
authors.initials: SM
authors.lastname: Hussein
authors.forename: Nizar N
authors.initials: NN
authors.lastname: Batada
authors.forename: Sanna
authors.initials: S
authors.lastname: Vuoristo
authors.forename: Reagan W
authors.initials: RW
authors.lastname: Ching
authors.forename: Reija
authors.initials: R
authors.lastname: Autio
authors.forename: Elisa
authors.initials: E
authors.lastname: Närvä
authors.forename: Siemon
authors.initials: S
authors.lastname: Ng
authors.forename: Michel
authors.initials: M
authors.lastname: Sourour
authors.forename: Riikka
authors.initials: R
authors.lastname: Hämäläinen
authors.forename: Cia
authors.initials: C
authors.lastname: Olsson
authors.forename: Karolina
authors.initials: K
authors.lastname: Lundin
authors.forename: Milla
authors.initials: M
authors.lastname: Mikkola
authors.forename: Ras
authors.initials: R
authors.lastname: Trokovic
authors.forename: Michael
authors.initials: M
authors.lastname: Peitz
authors.forename: Oliver
authors.initials: O
authors.lastname: Brüstle
authors.forename: David P
authors.initials: DP
authors.lastname: Bazett-Jones
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Riitta
authors.initials: R
authors.lastname: Lahesmaa
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: Timo
authors.initials: T
authors.lastname: Otonkoski
mesh_terms: D002460:Cell Line; D065150:Cellular Reprogramming / Q000235:genetics*; D043283:Chromosome Fragile Sites / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009030:Mosaicism; D016296:Mutagenesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics